title: Differential role of all-trans retinoic acid in promoting the development of CD4+ and CD8+ regulatory T cells.
abstract: It is known that ATRA promotes the development of TGF-β-induced CD4(+)Foxp3(+) iTregs, which play a vital role in the prevention of autoimmune diseases; however, the role of ATRA in facilitating the differentiation and function of CD8(+)Foxp3(+) iTregs remains elusive. Using a head-to-head comparison, we found that ATRA promoted expression of Foxp3 and development of CD4(+) iTregs, but it did not promote Foxp3 expression on CD8(+) cells. Using a standard in vitro assay, we demonstrated that CD8(+) iTregs induced by TGF-β and ATRA were not superior to CD8(+) iTregs induced by TGF-β alone. In cGVHD, in a typical lupus syndrome model where DBA2 spleen cells were transferred to DBA2xC57BL/6 F1 mice, we observed that both CD8(+) iTregs induced by TGF-β and ATRA and those induced by TGF-β alone had similar therapeutic effects. ATRA did not boost but, conversely, impaired the differentiation and function of human CD8(+) iTregs. CD8(+) cells expressed the ATRA receptor RAR and responded to ATRA, similar to CD4(+) cells. We have identified the differential role of ATRA in promoting Foxp3(+) Tregs in CD4(+) and CD8(+) cell populations. These results will help to determine a protocol for developing different Treg cell populations and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation.
authors.affiliation: 2.Penn State University Hershey College of Medicine, 500 University Drive, Hershey, PA 17033. szheng1@hmc.psu.edu; Division of Rheumatology, Immunology and Nephrology, Zhejiang Traditional Chinese Medicine and Western Medicine Hospital, 208 Huancheng East Road, Hangzhou 310003, P. R. China. E-mail: majilin0808@sohu.com.
authors.forename: Jilin
authors.initials: J
authors.lastname: Ma
authors.forename: Ya
authors.initials: Y
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.forename: Justin
authors.initials: J
authors.lastname: Liu
authors.forename: Jiayou
authors.initials: J
authors.lastname: Tang
authors.forename: Julie
authors.initials: J
authors.lastname: Wang
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.forename: David
authors.initials: D
authors.lastname: Brand
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016212:Transforming Growth Factor beta; D014212:Tretinoin
keywords: Autoimmunity; Foxp3; GVHD; TGF-β; all-trans retinoic acid; regulatory T cells